Poly (lactic-co-glycolic acid) (PLGA), a biodegradable and biocompatible FDA approved polymer, is being increasingly used in sustained drug delivery applications. Some biodegradable materials have been designed for glaucoma, however, these are generally implants that must reside in the eye and are limited in their delivery. Glaucoma drainage devices, for example, have been used for some time to release intraocular pressure by allowing flow of the aqueous humor from the anterior chamber of the eye. Some of these devices have been situated with therapeutics that can be released over time. However many of these formulations struggle with appropriate release profiles.
Reduction and control of the intraocular pressure (IOP) is the mainstay of treatment in the management of glaucoma. Elevated IOP can be reduced pharmacologically via daily eyedrops, or surgically by trabeculectomy and/or implantation of a glaucoma drainage device (GDD). What currently limits enthusiasm for GDDs is the development of inner wall bleb fibrosis, which hampers outflow facility and increases intraocular pressure. The success rate of GDD implants is ˜70% to 80% at one year and 40% to 50% five years postoperatively because of the development of fibrosis. A GDD that could regulate flow without the development of fibrosis could potentially become a first line treatment for glaucoma.
Invasiveness and metastatic dissemination characterize neuroectodermal tumors such as glioblastoma, neuroblastoma, medulloblastoma and melanoma. Despite the growing knowledge about their etiology and efforts to develop improved tools for early diagnosis and treatment, their invasive phenotype causes high mortality rate, especially among children and young adults. Brain tumors are particularly difficult to treat due to distinct anatomical and physiological traits of neural tissue and vasculature. The blood brain barrier (BBB) and blood-brain tumor barrier (BTB) represent the major obstacles that prevent chemotherapeutic agents from reaching intracranial tumors.
Several strategies have been developed to enhance the BBB and BTB permeability via biochemical intervention. Carotid artery infusion with hyperosmotic (1.6 M) mannitol was shown to temporarily open BBB, by induction of endothelial cells shrinkage and tight junction disruption. However, the opening lasts less than 30 minutes, leaving a very narrow window for potential drug delivery. Another strategy for more selective BTB opening involves the use of vasomodulators, mostly bradykinin or nitric oxide donors, which are able to transiently (for 15-120 minutes) increase capillary permeability. The main caveat associated with the use of bradykinin involves its ability to promote glioma cell migration, invasion and tumor angiogenesis and to act as a chemoattractant guiding glioma cells to the blood vessels. These effects increase aggressiveness of the tumor. For that reason, bradykinin B2 receptor antagonists have been proposed to be candidate anti-invasive drugs.
A number of unanswered questions remain about how to facilitate chemotherapeutic drug penetration and access to brain tumor tissue, and about how to develop new, more effective multidrug targeted regimens against glial tumors.